tbuckley/cabot-search huggingface dataset:
Selected Articles from This Issue
Journal: Clinical Cancer Research (2023)

Highlights| September 15 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (18): 3555. https://doi.org/10.1158/1078-0432.CCR-29-18-HI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record September 15 2023 Citation Selected Articles from This Issue. Clin Cancer Res 15 September 2023; 29 (18): 3555. https://doi.org/10.1158/1078-0432.CCR-29-18-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Treatment of chronic lymphocytic leukemia (CLL) with Bruton's tyrosine kinase inhibitors (BTKi), such as ibrutinib or acalabrutinib, has improved patient progression-free survival by disrupting B-cell receptor (BCR) signaling, suppressing CLL cell growth and survival, and blocking CLL cell adhesion to the microenvironment leading to increased lymphocytosis. A subunit of the integrin VLA-4/CD49d mediates adherence of CLL cells to the microenvironment by binding to VCAM-1 and, in patients treated with ibrutinib, high CD49d levels are correlated with reduced lymphocytosis and disinhibition of CLL adhesion. Alsadhan and colleagues demonstrated that, after acalabrutinib treatment, lymphocytosis diminished more quickly in CD49d+ CLL patients compared to CD49d− patients, likely due to insufficient inhibition of BCR inside-out activation. Through RNA sequencing data, the authors show increased NF-κB and JAK/STAT signaling, survival, and adhesion in CD49d+ cases compared to CD49d− cases. Interestingly, the authors found that most CLL cases that progressed on ibrutinib... You do not currently have access to this content.
Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine
Authors: Yang Zang, Shaorui Liu, Zebing Rao, Yinsheng Wang, Boya Zhang, Hui Li, Yingjiao Cao, Jie Zhou, Zhuxia Shen, Shengzhong Duan, Danyang He, Heping Xu
Journal: Immunity (2023)
Abstract PO-061: Utilizing T cell receptor-based therapy to treat anaplastic thyroid cancer
Authors: Shao-Hsi Hung, Ying Henderson, Ke Pan, Yulun Chiu, Shailbala Singh, Yunyun Chen, Stephen Lai, Cassian Yee
Journal: Clinical Cancer Research (2023)

Abstract Anaplastic thyroid cancer (ATC) is considered to be among the most aggressive solid tumors in thyroid tissue, with a 6-month medium overall survival. The effectiveness of conventional treatments, such as surgery, chemotherapy, and radiation therapy, in extending the survival of patients is limited. Therefore, there is an urgent need to develop novel systemic therapeutic interventions that can induce long-lasting responses. Adoptive cell therapy has revolutionized cancer immunotherapy by successfully treating B-cell malignancies through chimeric antigen receptor-based approaches. For solid tumors, there is a need to identify a broader spectrum of tumor target antigens, and the field has now shifted towards leveraging T cell receptors (TCRs) which can recognize both intracellular and extracellular antigen-derived epitopes displayed by major histocompatibility complex (MHC) molecules. Our team has established an immunogenic epitope discovery pipeline, followed by a specialized protocol for empiric validation of candidate epitopes. We characterized immunogenic epitopes by coupling tandem mass spectrometry of MHC-eluted peptides with tumor proteome and MHC-peptide binding prediction databases. By integrating multi-omics data (genomics, transcriptomics, and immunopeptidomics) from both in-house and publicly available ATC databases, we find that ATC exhibits significant upregulation of pathways associated with microtubule-based movement, chromosome segregation, kinetochore complex components, and mitotic cytokinesis. We have identified several HLA-A2- and A24-restricted immunogenic peptides representing these pathway-associated proteins that covered more than 60% of the patient population. NDC80 kinetochore complex components (NDC80) and PDZ binding kinase (PBK) have been selected as top candidates. Peptides derived from NDC80 and PBK were subsequently utilized to isolate antigen-specific T cells from peripheral blood and identify cognate TCR. These peptide-specific T lymphocytes elicit cytotoxicity toward multiple HLA-matched ATC cell lines and tumor samples in vitro and in vivo. Furthermore, understanding the role of these genes in ATC tumorigenesis may identify novel combination strategies with adoptive cell therapy to yield synergistic effects. In conclusion, our studies contribute to the development of a new treatment paradigm for treating ATC, with the prospect of improving survival and outcome in this rare cancer patient population. Citation Format: Shao-Hsi Hung, Ying Henderson, Ke Pan, Yulun Chiu, Shailbala Singh, Yunyun Chen, Stephen Lai, Cassian Yee. Utilizing T cell receptor-based therapy to treat anaplastic thyroid cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-061.
VP3-2023: Health-related quality of life (HRQoL) in the phase III NATALEE study of adjuvant ribociclib (RIB) plus a nonsteroidal aromatase inhibitor (NSAI) vs NSAI alone in patients (pts) with HR+/HER2- early breast cancer (EBC)
Authors: P.A. Fasching, D. Slamon, Z. Nowecki, B.D. Kukielka-Budny, D. Stroyakovskiy, D. Yardley, C. Huang, A. Chan, S. Chia, M. Martin, H.S. Rugo, S. Loi, S.A. Hurvitz, M. Untch, K. Afenjar, R. Fresco, A. Danyliv, I. Ferrusi, Z. Li, G.N. Hortobagyi
Journal: Annals of Oncology (2023)
Abstract PO-035: Immune profiles of long-term survivors of patients with head and neck squamous carcinoma on immune checkpoint inhibitor therapy
Authors: Brock Christensen, Min Kyung Lee, Ze Zhang, Rondi Butler, Geat Ramush, Kartik Sehgal, Keisuke Shirai, Devin Koestler, Lucas Salas, John Wiencke, Robert Haddad, Karl Kelsey
Journal: Clinical Cancer Research (2023)

Abstract Background: Only 15 – 20% of patients with head and neck squamous cell carcinoma (HNSCC) have response to anti-programmed cell death (PD)-1 immunotherapy and there remain gaps in predicting which patients will respond. Method: Here, we utilized DNA methylation cytometry to sequentially delineate detailed immune profiles of six patients with HNSCC (n=38 samples), who had durable response to immunotherapy over a one-year period without disease progression. Results: During the initial 3.5 months of anti-PD-1 immunotherapy treatment, increases in levels of CD8 T memory cells and natural killer cells were observed. Compared to healthy populations in similar age ranges, CD4 T and B cell levels were lower, while monocyte levels were higher in patients with HNSCC at baseline and throughout the year of treatment with immunotherapy. Conclusions: Our results suggest monitoring changes in immune cell type levels as potential biomarkers for patients with HNSCC who respond to anti-PD-1 immunotherapy. Citation Format: Brock Christensen, Min Kyung Lee, Ze Zhang, Rondi Butler, Geat Ramush, Kartik Sehgal, Keisuke Shirai, Devin Koestler, Lucas Salas, John Wiencke, Robert Haddad, Karl Kelsey. Immune profiles of long-term survivors of patients with head and neck squamous carcinoma on immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-035.
Abstract PO-016: SSTR2 use and molecular profile in EBV-positive nasopharyngeal carcinoma: A single institution experience
Authors: Juan J. Juarez-Vignon Whaley, Michelle Afkhami, Mykola Onyshchenko, Thomas Gernon, Robert Kang, Ellie Maghami, Sagus Sampath, Arya Amini, Diana Bell, Victoria M. Villaflor
Journal: Clinical Cancer Research (2023)

Abstract Background: Nasopharyngeal carcinoma (NPC) is a rare malignancy endemic in Southeast Asia. EBV infection is recognized as a major risk factor playing important roles in oncogenic pathways. Somatostatin receptor 2 (SSTR2) is a marker used in neuroendocrine tumors and appears to demonstrate high prevalence in EBV+ NPCs. Methods: We identified a total of 16 patients with biopsy-proven WHO type 3 EBV+ (via EBER) NPC in which SSTR2 expression via immunohistochemistry (IHC) was analyzed in either primary or metastatic lesions. Additionally, risk factors (smoking or alcohol), P16 via IHC, PD-L1 via IHC, tumor mutation burden (TMB), microsatellite instability (MSI), genomic alterations via Next Generation Sequencing (NGS), and time to progression (TTP) in months were reported. Results: Mean age of diagnosis was 60 years old, 14 were male, 13 were locally advanced and 37.5% former or heavy smokers. Ten patients were Asian with the rest being Latino (4), European (1) and unknown (1). Fourteen out of sixteen patients (87.5%) had SSTR2 expression either in primary lesions or metastatic lesions. P16 was measured in seven cases, all of them being negative. PDL1 was measured in 11 cases, 9 had high expression (≥ 20 CPS), 2 had expression (1-19 CPS) and 5 was not measured. In 10 cases TMB was evaluated, seven had low TMB and three intermediate TMB. From the TMB intermediate cases, all of them were MSI stable and two high PDL1 expression. From the 10 patients with MSI status all of them were stable. Out of the 16 patients, 11 patients had NGS performed from which 9 patients had clinically significant alterations. 4 out of 9 patients (44.4%) had an 11q13.2-13.3 amplification followed by 33.3% having a 9p21 loss and 22.2% TP53 mutation. Survival, median survival was not reached and median TTP was 23 months with the most common site being the liver. Conclusions: Given the high prevalence of SSTR2 in EBV+ NPCs (87.5%) in our cohort, SSTR2 via IHC may be a good screening tool for EBV + NPCs with potential diagnostic and therapeutic implications. 11q amplifications being present in 44.4% of our cohort might also be of diagnostic significance in NPC. Prognostic and clinical implications warrant further investigation. Citation Format: Juan J. Juarez-Vignon Whaley, Michelle Afkhami, Mykola Onyshchenko, Thomas Gernon, Robert Kang, Ellie Maghami, Sagus Sampath, Arya Amini, Diana Bell, Victoria M. Villaflor. SSTR2 use and molecular profile in EBV-positive nasopharyngeal carcinoma: A single institution experience [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-016.
Abstract PR07: Oncogene addition to MYB-NFIB in adenoid cystic carcinomas induced in transgenic mice
Authors: Vicente Escamilla-Rivera, Yuan Hu, Sungman Cho, Adel El-Naggar, Han Luo, Carlos Caulin
Journal: Clinical Cancer Research (2023)

Abstract Adenoid cystic carcinoma (ACC) is a slow-growing salivary gland malignancy. The frequent occurrence of chromosome t(6;9) translocations, resulting in MYB-NFIB fusions, is a hallmark of ACC. Approximately, 50% of all ACCs studied to date have been shown to express MYB-NFIB chimeric transcripts, suggesting a prominent role in ACC tumorigenicity. However, the potential relevance of chimeric MYB-NFIB proteins in the development and progression of ACC remains poorly understood. To assess the role of MYB-NFIB in ACC development, we generated transgenic mice in which MYB-NFIB is overexpressed in salivary and mammary glands, using a doxycycline-inducible system. Importantly, a subset of these mice developed ACCs, suggesting that MYB-NFIB is an oncogenic driver of ACC. Using this reversible inducible model, we investigated whether MYB-NFIB was required to maintain established tumors. We found that suppression of the MYB-NFIB transgene upon exposure to doxycycline (Dox) promoted a rapid tumor regression. Tumoral volumes decreased by more than 50 % after only 10 days of starting Dox. This reduction in volume was accompanied by a transition towards a more organized cellular structure and a reduction in the number of cells positive for Ki-67 and MYB-NFIB. To identify mechanisms involved in tumor regression, we compared the transcriptomes from biopsies collected from salivary tumors prior to MYB-NFIB suppression with those from the same tumors after Dox-induced regression. We found that tumor regression upregulated immune-related pathways and promoted T cell infiltration. Additionally, several pathways were downregulated by MYB-NFIB suppression; particularly NOTCH signaling, Cyclin D1-CDK4/6, and Wnt/beta-catenin signaling. We then confirmed, by immunohistochemistry, that tumor biopsies taken before Dox had a higher number of cells positive for Cdk6, CyclinD1, and nuclear beta-catenin. Our results suggest that proteins in these pathways could be used as potential therapeutic targets in MYB-NFIB-driven ACCs. Citation Format: Vicente Escamilla-Rivera, Yuan Hu, Sungman Cho, Adel El-Naggar, Han Luo, Carlos Caulin. Oncogene addition to MYB-NFIB in adenoid cystic carcinomas induced in transgenic mice [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR07.
Abstract PO-080: Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma
Authors: Minsu Kwon, Yoon Se Lee, Hanul Jung, Min Ji Kim, So Hee Kang, Ji-Hyun Seo, Jung Je Park
Journal: Clinical Cancer Research (2023)

Abstract The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC. Citation Format: Minsu Kwon, Yoon Se Lee, Hanul Jung, Min Ji Kim, So Hee Kang, Ji-Hyun Seo, Jung Je Park. Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-080.
Abstract PO-091: Leveraging tissue-resident CD103+ NK cells for adoptive cell therapy in head and neck cancer
Authors: Nina B. Horowitz, June Ho Shin, Sainiteesh Maddineni, Imran A. Mohammad, Alice Xinyuan Liu, John B. Sunwoo
Journal: Clinical Cancer Research (2023)

Abstract A major obstacle for all cell therapy of solid tumors has been the ability of adoptively transferred cells to infiltrate into immunosuppressive solid tumor microenvironments. In this study, we developed a method of differentiating and expanding a novel subset of tissue-resident natural killer (NK) cells and assessed their capacity to infiltrate head and neck squamous cell carcinoma (HNSCC) and control tumor growth in vivo. In previous work, single-cell RNA sequencing was performed to profile the entire innate lymphoid cell (ILC) family of lymphocytes (including NK cells) isolated from primary human head and neck squamous cell carcinoma (HNSCC). This revealed multiple subsets of NK cell and ILC states within the tumors. A particular NK cell state, resembling intraepithelial ILC1s (ieILC1), expressed integrins characteristic of tissue residency (such as CD103) and expressed the highest levels of granzyme A, granzyme B, and perforin, suggesting potent cytolytic activity. In the current study, we investigated the potential of these cells for adoptive cell immunotherapy against solid tumors, such as HNSCC and melanoma. Using a co-culture system, we developed a method to differentiate and expand a highly purified population of human CD103+ ieILC1-like NK cells ex vivo to clinically relevant numbers. In vitro impedance-based killing assays were used to assess and demonstrate that these cells have superior cytolytic activity against a variety of epithelial target cells, compared to conventional NK cells. In vivo mouse models using xenografts of HNSCC and melanoma in NSG mice were used to assess and demonstrate superior capacity of ieILC1-like NK cells to control tumor growth compared to conventional NK cells from the same donor. Importantly, the CD103+ ieILC1-like NK cells were able to infiltrate the tumor microenvironment significantly better than conventional NK cells, which likely contributed to their potent control of tumors in vivo. Thus, these findings introduce a novel subset of immune cells that have efficient tumor-infiltrating capacity and potent cytolytic activity for adoptive cell therapy of solid tumors. Because conventional NK cells have already demonstrated clinical activity, these preclinical data indicate that CD103+ ieILC1-like NK cells warrant investigation in the clinic. Citation Format: Nina B. Horowitz, June Ho Shin, Sainiteesh Maddineni, Imran A. Mohammad, Alice Xinyuan Liu, John B. Sunwoo. Leveraging tissue-resident CD103+ NK cells for adoptive cell therapy in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-091.
Abstract PR03: Cholinergic modulation of tumor infiltrating lymphocytes in oral squamous cell carcinoma
Authors: Ruth A. White
Journal: Clinical Cancer Research (2023)

Abstract Response to immunotherapy remains less than 20% for Oral Cavity Squamous Cell Carcinoma (OSCC). The poor response is in part due to dysfunctional cytotoxic T cell activity resulting from terminal exhaustion as a response to chronic exposure to tumor antigen. New strategies are needed to sensitize OSCC to immunotherapy to improve response rates and overall survival. Stimulation of muscarinic receptors by Acetylcholine (Ach), the primary neurotransmitter of the parasympathetic nervous system, restrains pancreatic and breast cancer but promotes gastric and late stage prostate cancer. The role of cholinergic signaling in OSCC is unknown. Ach can be secreted from non-neuronal tissues, including lymphocytes, which are abundant in the OSCC microenvironment. These lymphocytes express choline acetyltransferase (ChaT), the enzyme catalyzing the rate limiting step of Ach production and are important in maintaining chronic anti-viral immune responses. Our objective is to uncover the role of these Ach secreting T cells in mediating the anti-tumor immune response in OSCC. We utilized the 4MOSC1 and 4MOSC2 orthotopic OSCC tumor model. Orthotopic tumors were generated in recipient mice with impaired Ach-muscarinic signaling. ChaT+ CD8+ T cells were amplified in the tumor microenvironment and in vitro after activation. Inhibition of Ach-muscarinic signaling in the tumor immune microenvironment (TIME) accelerated tumor growth kinetics and was associated with loss of tumor infiltrating lymphocytes (TILs). Analysis of T cell activation states in TILs and after in vitro activation demonstrated that disruption of Ach-muscarinic signaling promotes differentiation of effector T lymphocytes at the expense of central memory. These data suggest that the Ach-muscarinic axis promotes CD8+ T cell infiltration and maintains T cell memory in the TIME supporting long term anti-tumor immune responses. Citation Format: Ruth A. White. Cholinergic modulation of tumor infiltrating lymphocytes in oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR03.
Abstract PO-084: Deletion of macrophage migration inhibitory factor promotes antitumoral T cell infiltration and inhibits MDSC recruitment to the head and neck cancer microenvironment
Authors: Steve Oghumu
Journal: Clinical Cancer Research (2023)

Abstract Head and neck squamous cell carcinoma (HNSCC) is a significant public health concern worldwide. Immunomodulatory targets in the HNSCC tumor microenvironment are crucial to enhance the efficacy of HNSCC immunotherapy. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been linked to worse prognosis in many cancers, but the mechanistic role of MIF in HNSCC remains unclear. Using a murine orthotopic oral cancer model in Mif+/+ or Mif− / − mice, we determined the function of host derived MIF in HNSCC tumor development, metastasis as well as localized and systemic tumor immune responses. We found that Mif− / − mice have decreased tumor growth and burden compared to their wild-type counterparts. Flow cytometric analysis of immune populations within the primary tumor site revealed increased T cell recruitment to the HNSCC tumor microenvironment, within the tumors of Mif− / − mice. MIF deletion also enhanced the effector function of anti-tumoral Th1 cells and decreased the accumulation of granulocytic MDSC in the tumor microenvironment. Furthermore, we show that isolated MDSC chemotactically respond to MIF in a dose dependent manner which is inhibited when MIF is depleted. Interestingly, MDSCs of tumor bearing Mif− / − mice expressed increased levels of PDL1 compared to Mif+/+ mice. However, Mif− / − and Mif+/+ MDSCs have comparable abilities to suppress T cell proliferation. Herein we describe a chemotactic and immunomodulatory role for MIF in the context of HNSCC. MIF targeted immunomodulation remains a potentially viable cancer therapeutic, however more remains to be understood about the cellular interaction of MIF within the tumor microenvironment before these targeted therapies can be effectively employed Citation Format: Steve Oghumu. Deletion of macrophage migration inhibitory factor promotes antitumoral T cell infiltration and inhibits MDSC recruitment to the head and neck cancer microenvironment [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-084.